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WO2020215356A1 - Utilisation d'acide pantothénique dans la préparation d'une composition pour le traitement et/ou la prévention de tumeurs - Google Patents

Utilisation d'acide pantothénique dans la préparation d'une composition pour le traitement et/ou la prévention de tumeurs Download PDF

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WO2020215356A1
WO2020215356A1 PCT/CN2019/085472 CN2019085472W WO2020215356A1 WO 2020215356 A1 WO2020215356 A1 WO 2020215356A1 CN 2019085472 W CN2019085472 W CN 2019085472W WO 2020215356 A1 WO2020215356 A1 WO 2020215356A1
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composition
pantothenic acid
tumor
application according
bacteroides
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Chinese (zh)
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蔡青青
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Revaissant Shenzhen Biosciences Co Ltd
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Revaissant Shenzhen Biosciences Co Ltd
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Priority to EP19926212.2A priority Critical patent/EP3960167A4/fr
Priority to US17/606,177 priority patent/US20220202754A1/en
Publication of WO2020215356A1 publication Critical patent/WO2020215356A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to the field of biomedicine, in particular to the application of pantothenic acid in the preparation of a composition for the treatment and/or prevention of tumors, and the use of pantothenic acid-containing intestinal bacterial metabolites in the preparation of a composition for the treatment and/or prevention of tumors
  • pantothenic acid-containing intestinal bacterial metabolites in the preparation of a composition for the treatment and/or prevention of tumors
  • intestinal bacteria capable of secreting metabolites containing pantothenic acid in the preparation of compositions for treating and/or preventing tumors.
  • tumor immunotherapy means to stimulate the body to produce a tumor-specific immune response through active or passive means, restore or enhance the activity of the body's immune system, relieve immunosuppression, and then curb the growth of tumor cells.
  • CD8+ killer T lymphocytes are one of the key immune cell subgroups for the body to exert anti-tumor function. At present, the effect of tumor immunotherapy is not good, mainly because the number of CD8+ killer T cells infiltrating in the tumor microenvironment is insufficient and the specificity is not strong.
  • T cell inhibitory molecule blocking antibodies which severely weakens the therapeutic effect. Therefore, it is urgent to develop new methods that can regulate the body's immune system functions, especially CD8+ killer T cells, NK cells, macrophages, regulatory T lymphocytes (Treg) and other immune cells in the tumor microenvironment.
  • the human intestinal flora can regulate the immune system from multiple aspects and play a vital role in the occurrence and development of diseases.
  • the intestinal flora and the human body are interdependent and interacting.
  • the human intestinal flora has the effect of inhibiting tumor growth and has broad application prospects for preventing and treating tumors.
  • the specific active substances of intestinal bacteria against tumors are currently not completely clear.
  • the intestinal flora decomposes and utilizes nutrients in the human intestine to produce many metabolites. These metabolites may be key active small molecules that inhibit tumors.
  • human intestinal bacterial metabolites enhance the accumulation of CD8+ killer T cells in the tumor microenvironment and are anti-tumor.
  • Pantothenic acid is also called vitamin B5, molecular formula: C 9 H 17 NO 5 , molecular weight is 219.23500, and it is a water-soluble vitamin. It was previously believed that pantothenic acid is mainly involved in the synthesis of Coenzyme A (CoA), and then participates in the synthesis and metabolism of carbohydrates, fats and proteins in the form of CoA. Pantothenic acid may have a certain protective effect on the skin and mucous membranes, but the mechanism of action is not clear. There is no research report on the use of pantothenic acid for anti-tumor, and there is no report on the use of pantothenic acid to enhance the accumulation of CD8+ killer T cells in the tumor microenvironment and anti-tumor.
  • CoA Coenzyme A
  • the purpose of the present invention is to address the above technical problems to be solved, especially for the problem of insufficient accumulation of CD8+ killer T lymphocytes in anti-tumor immune prevention and treatment, and to provide effective treatment and/or prevention of solid tumors, especially enhanced CD8+ killer T lymphocytes Compositions and/or methods for cell accumulation in the tumor microenvironment.
  • the present invention provides applications for treating and/or preventing tumors, and applications of pantothenic acid in preparing compositions for treating and/or preventing tumors.
  • the use can enhance the accumulation of CD8+ killer T lymphocytes in the tumor microenvironment to realize the anti-tumor effect. Therefore, the present invention also provides the application of pantothenic acid in preparing a composition for enhancing the accumulation of CD8-positive killer T lymphocytes in the tumor microenvironment.
  • the pantothenic acid of the present invention includes, but is not limited to, any of the following: stereoisomers, tautomers, geometric isomers, nitrogen oxide compounds, hydrates, solvates, metabolites, pharmacological Acceptable salts or prodrugs.
  • composition for treating and/or preventing tumors according to the present invention may be, but not limited to, a pharmaceutical composition or a food composition or a health care product composition.
  • the tumor of the present invention can be various solid tumors, such as but not limited to liver cancer, breast cancer, lung cancer, melanoma tumor, prostate cancer, fibrosarcoma, gastric cancer, esophageal cancer, colorectal cancer, bladder sarcoma, glioma and other entities Tumors, especially liver and/or breast tumors.
  • solid tumors such as but not limited to liver cancer, breast cancer, lung cancer, melanoma tumor, prostate cancer, fibrosarcoma, gastric cancer, esophageal cancer, colorectal cancer, bladder sarcoma, glioma and other entities Tumors, especially liver and/or breast tumors.
  • the present invention also provides the application of intestinal bacterial metabolites in the preparation of a composition for treating and/or preventing tumors, wherein the intestinal bacterial metabolites contain pantothenic acid.
  • the intestinal bacteria of the present invention include bacteria that contain pantothenic acid or secrete pantothenic acid during the growth process or their modifications or modifications, including but not limited to Prevotella Copri, Akkermansia muciniphila, and fragile bacteria.
  • Bacteroides fragilis Eubacterium, Alipis, Clostridium, Ruminococcus, Bifidobacterium saeculare, Bacteroides stercoris, False Bifidobacterium pseudocatenulatum, Butyricimonas virosa, Campylobacter ureolyticus, Enterobacter cloacae, Bacteroides ovatus, Fusobacterium variable (Fusobacterium varium), Bacteroides massiliensis, Bifidobacterium adolescentic, Parabacteroides goldsteinii, Sphingobacteria, Sutterella wadsworthensis Any one or more of.
  • the intestinal bacterial metabolite can be, but not limited to, any one or more of the following: intestinal bacterial culture supernatant; after genetic recombination, transformation or modification, attenuation, chemical treatment, physical treatment or inactivation Intestinal bacterial culture supernatant; and/or intestinal bacterial lysate.
  • the composition for treating and/or preventing tumors can be, but is not limited to, a pharmaceutical composition or a food composition or a health care product composition.
  • the present invention also provides the use of intestinal bacteria capable of secreting metabolites containing pantothenic acid in the preparation of compositions for treating and/or preventing tumors.
  • the metabolites can be, but are not limited to, any one or more of the following: intestinal bacteria culture supernatant; intestinal bacteria that have undergone genetic recombination, transformation or modification, attenuation, chemical treatment, physical treatment or inactivation Culture supernatant; and/or intestinal bacterial lysate.
  • the intestinal bacteria of the present invention include bacteria that contain pantothenic acid or secrete pantothenic acid during the growth process or their modifications or modifications, including but not limited to Prevotella Copri, Akkermansia muciniphila, and fragile bacteria.
  • Bacteroides fragilis Eubacterium, Alipis, Clostridium, Ruminococcus, Bifidobacterium saeculare, Bacteroides stercoris, False Bifidobacterium pseudocatenulatum, Butyricimonas virosa, Campylobacter ureolyticus, Enterobacter cloacae, Bacteroides ovatus, Fusobacterium variable (Fusobacterium varium), Bacteroides massiliensis, Bifidobacterium adolescentic, Parabacteroides goldsteinii, Sphingobacteria, Sutterella wadsworthensis Any one or more of.
  • the composition for treating and/or preventing tumors may be, but not limited to, a pharmaceutical composition or a food composition or a health care product composition.
  • the invention also provides the application of pantothenic acid in preparing a composition for enhancing the accumulation of CD8 positive (CD8+) killer T lymphocytes in the tumor microenvironment.
  • Endhancing the accumulation of CD8 positive killer T lymphocytes in the tumor microenvironment includes but is not limited to: the relative increase in the number of CD8+ T lymphocytes in all cells of the tumor microenvironment.
  • the pantothenic acid includes but is not limited to any one of the following: stereoisomers, tautomers, geometric isomers, nitrogen oxide compounds, hydrates, solvates, metabolites, pharmaceutically acceptable
  • stereoisomers tautomers
  • geometric isomers nitrogen oxide compounds, hydrates, solvates, metabolites, pharmaceutically acceptable
  • composition for treating and/or preventing tumors according to the present invention may be, but not limited to, a pharmaceutical composition or a food composition or a health care product composition.
  • the tumor of the present invention can be various solid tumors, such as but not limited to liver cancer, breast cancer, lung cancer, melanoma tumor, prostate cancer, fibrosarcoma, gastric cancer, esophageal cancer, colorectal cancer, bladder sarcoma, glioma and other entities Tumors, especially liver and/or breast tumors.
  • solid tumors such as but not limited to liver cancer, breast cancer, lung cancer, melanoma tumor, prostate cancer, fibrosarcoma, gastric cancer, esophageal cancer, colorectal cancer, bladder sarcoma, glioma and other entities Tumors, especially liver and/or breast tumors.
  • the present invention also provides the use of intestinal bacterial metabolites in the preparation of a composition for enhancing the accumulation of CD8 positive (CD8+) killer T lymphocytes in the tumor microenvironment, characterized in that: the intestine
  • the bacterial metabolites contain pantothenic acid.
  • the present invention also provides the use of enteric bacteria capable of secreting metabolites containing pantothenic acid in the preparation of a composition for enhancing the accumulation of CD8-positive (CD8+) killer T lymphocytes in the tumor microenvironment.
  • the present invention also provides a composition for treating and/or preventing tumors, which contains pantothenic acid as an active ingredient of the drug.
  • the composition is a pharmaceutical composition comprising pantothenic acid and a pharmaceutically acceptable carrier thereof.
  • the tumor may be various solid tumors, such as, but not limited to, liver cancer, breast cancer, lung cancer, melanoma tumor, prostate cancer, fibrosarcoma, gastric cancer, esophageal cancer, colorectal cancer, bladder sarcoma, glioma and other solid tumors, Especially liver and/or breast tumors.
  • the intestinal bacteria include bacteria containing pantothenic acid or secreting pantothenic acid during growth, or their transformations or modifications, including but not limited to Prevotella Copri , Akkermansia muciniphila, Bacteroides fragilis, Eubacterium, Alistipes, Clostridium, Ruminococcus, Bifidobacterium saeculare), Bacteroides stercoris, Bifidobacterium pseudocatenulatum, Butyricimonas virosa, Campylobacter ureolyticus, Enterobacter cloacae, Ovum Bacteroides ovatus, Fusobacterium varium, Bacteroides massiliensis, Bifidobacterium adolescentic, Parabacteroides goldsteinii, Sphingobacteria ), any one or more of Sutterella wadsworthensis.
  • Prevotella Copri Akkermansia muciniphila
  • Bacteroides fragilis Eubacter
  • the intestinal bacterial metabolites include but are not limited to any one or more of the following: intestinal bacterial culture supernatant; after genetic recombination, transformation or modification, Attenuated, chemically treated, physically treated or inactivated intestinal bacterial culture supernatant; and/or intestinal bacterial lysate.
  • pantothenic acid in the above pharmaceutical composition, may be, but not limited to, any one or more of the following: stereoisomers, tautomers, geometric isomers, and nitrogen oxide compounds of pantothenic acid , Hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs.
  • the pharmaceutical composition of the present invention includes a pharmaceutically effective dose of pantothenic acid and a pharmaceutically acceptable carrier thereof.
  • pantothenic acid is the active ingredient.
  • the pharmaceutical composition may be any one or more dosage forms that are pharmaceutically feasible, including but not limited to tablets, capsules, oral liquids or freeze-dried powders.
  • the pharmaceutically acceptable carrier is skimmed milk, lactose, glucose, sucrose, sorbitol, mannose, trehalose, starch, acacia, calcium phosphate, alginate, gelatin , Calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or one of mineral oil One or more mixtures.
  • the composition may also be an edible composition, and the edible composition includes, but is not limited to, food, health care products, food additives, and the like.
  • the present invention also provides a composition for enhancing the accumulation of CD8-positive killer T lymphocytes in the tumor microenvironment, the composition containing pantothenic acid as an active ingredient.
  • the composition is a pharmaceutical composition comprising pantothenic acid and a pharmaceutically acceptable carrier thereof.
  • the tumor may be various solid tumors, such as, but not limited to, liver cancer, breast cancer, lung cancer, melanoma tumor, prostate cancer, fibrosarcoma, gastric cancer, esophageal cancer, colorectal cancer, bladder sarcoma, glioma and other solid tumors, Especially liver and/or breast tumors.
  • the intestinal bacteria include bacteria containing pantothenic acid or secreting pantothenic acid during growth, or their transformations or modifications, including but not limited to Prevotella Copri , Akkermansia muciniphila, Bacteroides fragilis, Eubacterium, Alistipes, Clostridium, Ruminococcus, Bifidobacterium saeculare), Bacteroides stercoris, Bifidobacterium pseudocatenulatum, Butyricimonas virosa, Campylobacter ureolyticus, Enterobacter cloacae, Ovum Bacteroides ovatus, Fusobacterium varium, Bacteroides massiliensis, Bifidobacterium adolescentic, Parabacteroides goldsteinii, Sphingobacteria ), any one or more of Sutterella wadsworthensis.
  • Prevotella Copri Akkermansia muciniphila
  • Bacteroides fragilis Eubacter
  • the intestinal bacterial metabolites include but are not limited to any one or more of the following: intestinal bacterial culture supernatant; after genetic recombination, transformation or modification, Attenuated, chemically treated, physically treated or inactivated intestinal bacterial culture supernatant; and/or intestinal bacterial lysate.
  • pantothenic acid in the above pharmaceutical composition, may be, but not limited to, any one or more of the following: stereoisomers, tautomers, geometric isomers, and nitrogen oxide compounds of pantothenic acid , Hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs.
  • the pharmaceutical composition of the present invention includes a pharmaceutically effective dose of pantothenic acid and a pharmaceutically acceptable carrier thereof.
  • pantothenic acid is the active ingredient.
  • the pharmaceutical composition may be any one or more dosage forms that are pharmaceutically feasible, including but not limited to tablets, capsules, oral liquids or freeze-dried powders.
  • the pharmaceutically acceptable carrier is skimmed milk, lactose, glucose, sucrose, sorbitol, mannose, trehalose, starch, acacia, calcium phosphate, alginate, gelatin , Calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or one of mineral oil One or more mixtures.
  • the composition may also be an edible composition, and the edible composition includes, but is not limited to, food, health care products, food additives, and the like.
  • composition of the present invention can realize the anti-tumor effect by enhancing the accumulation of CD8+ killer T lymphocytes in the tumor microenvironment.
  • the present invention establishes a mouse liver cancer model by the transplantation tumor research method.
  • the present invention proves through experiments that the intestinal bacterial metabolite—pantothenic acid can significantly inhibit liver tumors. It can effectively inhibit the growth of transplanted tumors in mice, suggesting that pantothenic acid, a metabolite of intestinal bacteria, has important development and application value in the clinical treatment of tumors.
  • Figure 1 is a schematic diagram of the experimental process of detecting intestinal bacteria (Pr.
  • the time to administer intestinal bacteria (Prevotella as an example) or transplant tumor cells is expressed in days (Day, d).
  • Figure 2 shows the relative quantitative statistics of pantothenic acid in the intestinal bacterial metabolite screening test.
  • Figure 3 is a schematic diagram of the experimental procedure for detecting the intestinal bacterial metabolite pantothenic acid to enhance the accumulation of CD8+ killer T lymphocytes in the tumor microenvironment and anti-tumor in a mouse liver cancer model.
  • the time of administration of pantothenic acid or transplantation of tumor cells is expressed in days (Day, d).
  • Figure 4 is a comparison diagram of tumor size of 3 typical mouse liver cancer cell transplanted tumors in each group after pantothenic acid treatment.
  • Figure 5 is a statistical analysis diagram of the tumor size comparison of 9 typical mouse liver cancer cell transplanted tumors in each group after pantothenic acid treatment.
  • Figure 6 is a flow cytometric analysis diagram of typical CD8-positive T lymphocytes of one mouse in each group after administration of pantothenic acid to liver tumors of mice transplanted with liver cancer cells.
  • the lower right quadrant shows CD8-positive T lymphocytes, and the lower right side
  • the numbers in the quadrants show the percentage of CD8-positive T lymphocytes in the total cells in the liver tumor microenvironment.
  • Figure 7 is a statistical analysis diagram of the percentage of CD8-positive T lymphocytes in the total cells in the tumor microenvironment after pantothenic acid administration in mice transplanted with liver cancer cells.
  • the present invention will be further described below in conjunction with specific embodiments. It should be pointed out that the intestinal bacterial metabolite used for anti-tumor in the present invention-pantothenic acid or the pharmaceutical composition, food, health care products and food additives containing the intestinal bacterial metabolite pantothenic acid of the present invention are applied to the test subjects. After that, it can be applied to the above-mentioned indications and exhibit the above-mentioned functions. All dosage forms within the scope of the present invention have been tested. The following is only for illustration and only described in the examples. A small part of it should not be construed as a limitation of the present invention.
  • the intestinal bacteria referred to in the present invention include but are not limited to any one of the following: Prevotella Copri, Akkermansia muciniphila, Bacteroides fragilis, Eubacterium , Alipis, Clostridium, Ruminococcus, Bifidobacterium saeculare, Bacteroides stercoris, Bifidobacterium pseudocatenulatum, Chlorophyllum Butyricimonas virosa, Campylobacter ureolyticus, Enterobacter cloacae, Bacteroides ovatus, Fusobacterium varium, Bacteroides massiliensis ), Bifidobacterium adolescentic, Parabacteroides goldsteinii, Sphingobacteria, Sutterella wadsworthensis and other bacteria that contain pantothenic acid or secrete pantothenic acid during the growth process. The modification or modification of the bacteria.
  • the intestinal bacteria include, but are not limited to
  • intestinal bacterial metabolite is a metabolite produced by intestinal bacteria (such as human intestinal bacteria), which includes but is not limited to any one or more of the following: intestinal bacterial culture supernatant Intestinal bacterial culture supernatant that has undergone genetic recombination, transformation or modification, attenuation, chemical treatment, physical treatment or inactivation; and/or intestinal bacterial lysate.
  • pantothenic acid includes but is not limited to any of the following: stereoisomers, tautomers, geometric isomers, nitrogen oxide compounds, hydrates, solvents of pantothenic acid Compounds, metabolites, pharmaceutically acceptable salts or prodrugs.
  • the tumor is a solid tumor, such as but not limited to liver cancer, breast cancer, melanoma tumor, lung cancer, prostate cancer, fibrosarcoma, gastric cancer, esophageal cancer, bladder sarcoma, glioma and other solid tumors.
  • the tumor includes, but is not limited to: liver cancer.
  • the present invention also provides a pharmaceutical composition for treating and/or preventing tumors, which includes pantothenic acid, a pharmaceutically effective dose of the intestinal bacterial metabolite.
  • the so-called “pharmaceutical effective dose” is 0.01 to 0.1 g/ml, preferably 0.01 to 0.02 g/ml, 0.01 to 0.03 g/ml, 0.01 to 0.04 g/ml, 0.01 to 0.05 g/ml, 0.01 ⁇ 0.06g/ml, 0.01 ⁇ 0.07g/ml, 0.01 ⁇ 0.08g/ml, 0.01 ⁇ 0.09g/ml, most preferably 0.02g/ml.
  • the pharmaceutical composition can be a variety of different formulations, including but not limited to tablets, capsules, oral liquids or freeze-dried powders.
  • the pharmaceutically acceptable carrier includes, but is not limited to, skimmed milk, lactose, glucose, sucrose, sorbitol, acacia, mannose, starch, trehalose, calcium phosphate, alginate, gelatin, calcium silicate, One or more of fine crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil.
  • the intestinal bacterial metabolite "pantothenic acid" of the present invention can also be made into food, health care products or food additives.
  • Said foods, health products or food additives all contain stereoisomers, tautomers, geometric isomers, nitrogen oxide compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or precursors of pantothenic acid. Any one or more of medicines.
  • These foods, health products or food additives can be used to treat and/or prevent tumors.
  • Figure 1 is a schematic diagram of the experimental process of detecting intestinal bacteria to treat tumors.
  • This embodiment takes Prevotella Copri as an example, but the technical solution of the present invention is not limited to Prevotella, but also includes Myxobacterium Ackermann, Bacteroides fragilis, Eubacteria, Alternaria, Clostridium, Rumenococcus , Century Bifidobacterium, Bacteroides faecalis, Bifidobacterium pseudostriata, Bifidobacterium aeruginosa, Campylobacter urealyticum, Bacteroides cloacae, Bacteroides ovatus, Fusarium variabilis, Bacteroides faecalis, Bifidobacterium adolescentis Intestinal bacteria such as bacillus, Subsidiary bacillus, Sphingosine and Waltersarter. These intestinal bacteria all have the common characteristics of containing pantothenic acid or secreting pantothenic acid during their growth.
  • Step 1 Take a lyophilized Prevotella copri (purchased from the ATCC official website), add 200 ⁇ l PYG medium, reconstitute, draw 20 ⁇ l, streak blood plate, anaerobic tank gas control system After airing, in a biochemical incubator at 37 degrees Celsius, anaerobic culture for 48 hours;
  • Step 2 Pick a single colony into 10ml PYG medium, 37 degrees Celsius, anaerobic culture for 12 hours;
  • Step 3 Take 1 bottle of 500 ml PYG medium, insert 1% (v/v) strains, 37 degrees Celsius, anaerobic culture for 48 hours;
  • Step 4 Take the bacteria liquid and centrifuge at 6000rpm for 10min. The culture supernatant after centrifugation was frozen and stored at -80 degrees Celsius. The bacterial sludge was washed twice with physiological saline, and finally the bacterial sludge was reconstituted with physiological saline for use and counted live bacteria.
  • This implementation case takes Prevotella Copri as an example, but it is not limited to Prevotella, but also includes Ackerman myxobacteria, Bacteroides fragilis, Eubacterium, Alternaria, Clostridium, Rumenococcus, Bifidobacterium century , Bacteroides faecalis, Bifidobacterium pseudo-small-chain, Bifidobacterium aeruginosa, Campylobacter urealyticum, Bacteroides cloacae, Bacteroides ovatus, Fusobacterium variable, Bacteroides tuber, Bifidobacterium adolescentis, Golden stevia Intestinal bacteria such as Bacillus sp., Sphingomyces, Wardesatella.
  • Ackerman myxobacteria Bacteroides fragilis, Eubacterium, Alternaria, Clostridium, Rumenococcus, Bifidobacterium century , Bacteroides fa
  • mice 18 C57BL/6 mice with good mental state for 3 to 4 weeks, purchased from the Experimental Animal Center of Sun Yat-sen University. The mice were randomly divided into 2 groups, 9 in each group. The 2 groups were the control group and the viable bacteria gavage group. The 2 groups of mice were gavaged with normal saline and 10 9 CFU of Prevotella for 4 consecutive gavages. .
  • mice tumor liver cancer
  • HEPA1-6 grow to the logarithmic phase, the cells are digested with trypsin, then neutralized with the medium, the cells are collected after centrifugation, washed twice with DPBS to remove residual serum, and finally reconstituted with DPBS Hanging cells.
  • mice After counting the cells, 10 6 cells were inoculated into the right armpit of each mouse. The mice were given intragastric administration (1 ⁇ 10 9 , 200 ⁇ l, 5/6/7/8/9 times). After 2 weeks, the tumor-bearing mice were sacrificed. The tumor size of the mice was counted and the inhibition was calculated. Tumor rate.
  • Fig. 1 The experimental procedure of intestinal bacteria treatment for mice with transplanted liver cancer cells is shown in Fig. 1, taking Prevotella as an example, but not limited to Prevotella.
  • the time to administer intestinal bacteria (Prevotella as an example) or transplant tumor cells is expressed in days (Day, d).
  • mice compared with the normal saline control group, the tumor volume of mice was significantly reduced by about 40-88% after the administration of Prevotella, and the reduction was statistically different (p ⁇ 0.05).
  • Ackermann myxobacteria (tumor inhibition rate ⁇ 40% to 80%), Bacteroides fragilis (tumor inhibition rate ⁇ 40% to 85%) , Eubacterium (tumor inhibition rate ⁇ 31% to 66%), alternative mycobacteria (tumor inhibition rate ⁇ 27% to 63%), Clostridia (tumor inhibition rate ⁇ 29% to 78%), rumen cocci (tumor inhibition rate ⁇ 35% ⁇ 78%), Century Bifidobacterium (tumor inhibition rate ⁇ 28% ⁇ 71%), Bacteroides faecalis (tumor inhibition rate ⁇ 33% ⁇ 62%), pseudosmall chain Bifidobacterium (tumor inhibition rate ⁇ 26% ⁇ 56%), Cyclobutyricum (tumor inhibition rate ⁇ 31% ⁇ 53%), Campylobacter urealyticum (tumor inhibition rate ⁇ 30% ⁇ 62%), cloaca
  • the implementation case takes Prevotella copri as an example, but it is not limited to Prevotella, but also includes Ackerman myxobacteria, Bacteroides fragilis, Eubacterium, Alternaria, Clostridium, Rumenococcus, Bifidobacterium century, Bacteroides faecalis, Bifidobacterium pseudo-small-chain, Bacillus chlorobutyricum, Campylobacter urealyticum, Bacteroides cloacae, Bacteroides ovatus, Fusobacterium variabilis, Bacteroides tuberosus, Bifidobacterium adolescentis, A. aureum Intestinal bacteria such as sphingosine bacillus and wadesatella.
  • Step 1 Take a lyophilized Prevotella copri (purchased from the ATCC official website), add 200 ⁇ l PYG medium, reconstitute, draw 20 ⁇ l, streak blood plate, anaerobic tank gas control system After airing, in a biochemical incubator at 37 degrees Celsius, anaerobic culture for 48 hours;
  • Step 2 Pick a single colony into 10ml PYG medium, 37 degrees Celsius, anaerobic culture for 12 hours;
  • Step 3 Take 1 bottle of 500 ml PYG medium, insert 1% (v/v) strains, 37 degrees Celsius, anaerobic culture for 48 hours;
  • Step 4 Take the bacteria liquid and centrifuge at 6000rpm for 10min. Take the centrifuged culture supernatant and freeze it at -80 degrees Celsius, wash the bacterial mud twice with normal saline, and finally reconstitute the bacterial mud with normal saline for use and count the viable bacteria to quantify the concentration of the supernatant.
  • the implementation case takes Prevotella copri as an example, but it is not limited to Prevotella, but also includes Ackerman myxobacteria, Bacteroides fragilis, Eubacterium, Alternaria, Clostridium, Rumenococcus, Bifidobacterium century, Bacteroides faecalis, Bifidobacterium pseudo-small-chain, Bacillus chlorobutyricum, Campylobacter urealyticum, Bacteroides cloacae, Bacteroides ovatus, Fusobacterium variabilis, Bacteroides tuberosus, Bifidobacterium adolescentis, A. aureum Intestinal bacteria such as sphingosine bacillus and wadesatella.
  • Intestinal bacteria culture supernatant grouping the control group is pure medium (PYG medium), and the experimental group is Prevotella culture supernatant, with 6 replicates in each group.
  • methoxyamine salt reagent methoxyamine hydrochloride, dissolved in pyridine 20mg/mL
  • V 4.3x Data analysis Chroma TOF software (V 4.3x, LECO) was used to analyze the mass spectrum data such as peak extraction, baseline correction, deconvolution, peak integration, and peak alignment.
  • LECO-Fiehn Rtx5 database was used, including mass spectrometry matching and retention time index matching.
  • the experimental group Ackerman myxobacteria (increased peak area ⁇ 80%), Bacteroides fragilis (increased peak area ⁇ 90%), Eubacteria (increased peak area ⁇ 81%), other mycobacteria (increased peak area ⁇ 75%), Clostridia (increased peak area by 65%), rumen cocci (increased peak area ⁇ 68%) ), Century Bifidobacterium (increased peak area ⁇ 65%), Bacteroides faecalis (increased peak area ⁇ 72%), pseudo-small chain Bifidobacterium (increased peak area ⁇ 52%), green butyric acid cell Bacteria (increased peak area ⁇ 51%), Campylobacter urealyticum (increased peak area ⁇ 75%), Cloacae (increased peak area ⁇ 58%), Bacteroides ovatus (in
  • pantothenic acid during the above-mentioned bacterial culture indicates that the intestinal bacteria produce and secrete a large amount of pantothenic acid, which is one of the key active small molecular substances for the intestinal bacteria to inhibit tumor.
  • Example 3 Pantothenic acid enhances the accumulation of CD8+ killer T lymphocytes in the tumor microenvironment and anti-tumor experiment
  • FIG 3 is a schematic diagram of the experimental procedure for detecting the intestinal bacterial metabolite pantothenic acid to enhance the accumulation of CD8+ killer T cells in the tumor microenvironment and the treatment of tumors in a mouse liver cancer model. That is, the experimental procedure of administering pantothenic acid to mice after subcutaneously transplanted liver cancer cells (HEPA1-6). Among them, the time of administration of pantothenic acid or transplantation of tumor cells is expressed in days (Day, d).
  • HEPA1-6 subcutaneously transplanted liver cancer cells
  • mice 27 C57BL/6 mice purchased from the Experimental Animal Center of Sun Yat-sen University at 3 to 4 weeks, with good mental state.
  • the mice were randomly divided into 3 groups, 9 in each group, namely the control group, the pantothenic acid group, and the vitamin E group.
  • the 3 groups of mice were given pure water, pantothenic acid (concentration 0.02g/ml, purchased from the Sigma official website) and vitamin E. (Concentration 0.02g/ml, purchased from Sigma official website), continue to drink the drug for 3 to 4 weeks.
  • mice HEPA1-6 grow to the logarithmic phase, the cells are digested with trypsin, the culture medium is added to neutralize the trypsin, the cells are collected after centrifugation, washed twice with DPBS to remove residual serum, and finally reconstituted with DPBS Hanging cells.
  • mice per 10 6 cells were inoculated subcutaneously to the right armpit. The mice continued to be treated with drugs.
  • the tumor-bearing mice were sacrificed. After dissection, the size of the subcutaneous transplanted tumor was measured, tumor cells were collected in situ, and the CD8 positive T in the tumor microenvironment was detected and analyzed by flow cytometry. The relative number of lymphocytes.
  • Figure 4 is a comparison diagram of tumor size of 3 typical mouse liver cancer cell transplanted tumors in each group after administration of pantothenic acid.
  • Figure 5 shows the statistical analysis results of the size and volume of 9 typical mouse liver cancer cell transplanted tumors in each group after administration of pantothenic acid. From the experimental results of Figure 4 and Figure 5, it can be clearly observed that after the administration of pantothenic acid, the volume of transplanted liver cancer cells was greatly reduced by about 80%, and the reduction was statistically significant (p ⁇ 0.01). It can be concluded that the treatment of pantothenic acid can significantly inhibit tumor growth.
  • Figure 6 is a flow cytometric analysis of the number of CD8-positive T lymphocytes in a typical liver cancer cell transplanted tumor microenvironment of one mouse in each group after administration of pantothenic acid.
  • the lower right quadrant is the CD8-positive T lymphocytes, and the lower right quadrant is The figure shows the percentage of CD8-positive T lymphocytes in all cells in the liver tumor microenvironment.
  • pantothenic acid compared with the vitamin E control group, pantothenic acid increased the relative amount of CD8+ T lymphocytes in the liver tumor microenvironment by more than 3 times. Compared with the pure water control group, it increased the CD8+ T lymphocytes. The relative amount of cells increased by more than 7 times.
  • Figure 7 is a statistical analysis diagram of the percentage of CD8+ T lymphocytes in tumor microenvironment cells after administration of pantothenic acid in mice transplanted with liver cancer cells. It can be seen from the statistical graph that compared with the pure water control group and the vitamin E control group, pantothenic acid significantly increased the relative number of CD8+ T lymphocytes in the tumor microenvironment, and the increase was statistically significant (p ⁇ 0.05).
  • ns indicates that the difference is not statistically significant
  • * indicates student t-test p ⁇ 0.05
  • ** indicates student t-test p ⁇ 0.01
  • **** indicates student t-test p ⁇ 0.0001 .
  • p ⁇ 0.05 has statistical significance.
  • the supernatant experiment has 6 replicates in each treatment group, and the animal experiment has 9 mice in each treatment group.
  • pantothenic acid can affect mouse tumors ( The formation and growth of hepatocarcinoma xenograft tumors are significantly inhibited ( Figure 4, Figure 5).
  • pantothenic acid promotes the accumulation of CD8-positive T lymphocytes in the tumor microenvironment in vivo, thereby inhibiting tumor growth and can be effectively treated And/or prevent tumors (especially liver tumors).

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Abstract

La présente invention concerne l'utilisation d'acide pantothénique dans la préparation d'une composition pour le traitement et/ou la prévention de tumeurs. La présente invention concerne également l'utilisation du métabolite bactérien intestinal contenant de l'acide pantothénique dans la préparation d'une composition pour le traitement et/ou la prévention de tumeurs. La présente invention concerne également l'utilisation des bactéries intestinales capables de sécréter des métabolites contenant de l'acide pantothénique dans la préparation d'une composition pour le traitement et/ou la prévention de tumeurs. L'acide pantothénique et le métabolite bactérien intestinal contenant de l'acide pantothénique peuvent favoriser l'accumulation de lymphocytes T tueurs CD8+ dans le micro-environnement tumoral, inhiber la croissance tumorale, et obtenir un effet de prévention et/ou de traitement de tumeurs.
PCT/CN2019/085472 2019-04-25 2019-05-05 Utilisation d'acide pantothénique dans la préparation d'une composition pour le traitement et/ou la prévention de tumeurs Ceased WO2020215356A1 (fr)

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CN116949165B (zh) * 2023-06-25 2024-04-02 大连医科大学 用于评估焦虑/抑郁-乳腺癌共患病的粪便标志物组及其应用
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